(19) & (11) EP 2 283 865 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 16.02.2011 Bulletin 2011/07 A61K 47/12 (2006.01) A61K 47/32 (2006.01) A61P 5/24 (2006.01) A61K 31/568 (2006.01) (21) Application number: 10184108.8 (22) Date of filing: 29.08.2001 (84) Designated Contracting States: • LABORATOIRES BESINS INTERNATIONAL AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU 75003 Paris (FR) MC NL PT SE TR Designated Extension States: (72) Inventor: Dudley, Robert E. AL LT LV MK RO SI Florida, il 32461 (US) (30) Priority: 30.08.2000 US 651777 (74) Representative: Cabinet Plasseraud 01.11.2000 US 703753 52, rue de la Victoire 21.05.2001 US 292398 P 75440 Paris Cedex 09 (FR) (62) Document number(s) of the earlier application(s) in Remarks: accordance with Art. 76 EPC: This application was filed on 30-09-2010 as a 01964525.8 / 1 322 336 divisional application to the application mentioned under INID code 62. (71) Applicants: • Unimed Pharmaceuticals, LLC Marietta, GA 30062 (US) (54) Method of increasing testosterone and related steroid concentrations in women (57) The present invention relates to methods, kits, venting, or reducing the risk of developing a testosterone combinations, and compositions for treating, preventing deficient disorder. The methods, kits, combinations and or reducing the risk of developing a testosterone deficient compositions can also be used in conjunction with a phar- disorder, or the symptoms associated with, or related to macologically effective amount of an estrogenic hor- a testosterone deficient disorder in a female mammal in mone, for example, estradiol. Furthermore, the methods, need thereof. The present invention also relates to a kits, combinations and compositions can be used in con- method of administering a steroid in the testosterone syn- junction with a pharmacologically effective amount of an- thetic pathway, for example testosterone, to a mammal other steroid or pharmaceutical agent that increases se- in need thereof. In addition, the methods, kits, combina- rum testosterone levels in a mammal, for example, meth- tions and compositions may be used in conjunction with yltestosterone. other pharmaceutical agents effective at treating, pre- EP 2 283 865 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 283 865 A1 Description FIELD OF THE INVENTION 5 [0001] The present invention is related to methods, kits, combinations, and compositions for transdermally delivering an effective amount of testosterone using a hydroalcoholic gel formulation. DESCRIPTION OF THE RELATED ART 10 [0002] Transdermal preparations of testosterone have provided a useful delivery system for normalizing serum tes- tosterone levels in hypogonadal men and preventing the clinical symptoms and long term effects of androgen deficient men. Available transdermal preparations of testosterone include, for example, TESTODERM®, TESTODERM® TTS, and ANDRODERM®. Testosterone is also available in other formulations including those available as an injectable, for example, DEPO-TESTOSTERONE® (testosterone cypionate), and DELATESTRYL BTG® (testosterone enanthate), 15 or as a gel, for example, ANDROGEL® marketed by Unimed Pharmaceuticals, Inc., Deerfield, Illinois, the assignee of this application. [0003] In men, transdermal patches are applied to the scrotal skin or other parts of the body. Recently, a one- percent testosterone gel has been approved for use in men, and provides dosing flexibility with minimal skin irritation. This gel is marketed under the name ANDROGEL®. However, all currently available testosterone transdermal products are 20 specifically contraindicated for use in women in the United States. Furthermore, none of the currently available androgen treatment modalities for women, for example, oral methyltestosterone, intramuscular testosterone ester injections or subcutaneous testosterone implants can achieve reproducible testosterone serum levels on a consistent daily basis. A. Testosterone Physiology in Women 25 [0004] The excretion of androgenic steroids in the urine of adult women was demonstrated more than 50 years ago. Since that time, physiologists and clinicians have explored the sources and biological functions of testosterone and other endogenous androgenic hormones in the human female, see, for example, Geist S.H., Androgen therapy in the human female, J. Clin. Endocrinol. 1941; 1:154-161. It is now known that androgens are secreted by both the ovaries and 30 adrenal glands in women. Each source contributes about 50% (directly and through precursors) (see, for example, Abraham G.E., Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle, J. Clin. Endocrinol. Metab. 1974; 39:340-346) to the approximately 300 Pg of testosterone produced daily in healthy "cycling" women (see, for example, Southren A. L., et al., Further study of factors affecting the metabolic clearance rate of testosterone in man, J. Clin. Endocrinol. Metab. 1968; 28:1105-1112). While the adverse effects of excess androgen production, as occurs 35 in the polycystic ovary syndrome and certain androgen producing tumors, have been well described (see, for example, Lobo R.A., Chapter 20: Androgen excess in Infertility, Contraception and Reproductive Endocrinology, Third Edition. DR Mishell, V. Davajan and R. Lobo, Editors. Blackwell Scientific Publications, Boston. pp 422-446,1991), the normal physiological effects of androgens in women have been much less appreciated. As inferred from animal studies, male physiology, and the symptoms of women with deficient androgen production, the major physiological effects of androgens 40 in normal women include, but are not limited to anabolic effects on muscle, skin, hair and bone; stimulatory effects on erythropoiesis; modulatory effects on immune function; and psychological effects on mood, well-being and sexual func- tion. [0005] In addition, endogenous androgens are important for the development of pubic hair and are thought to modulate the action of estrogens and progestins on a variety of reproductive target tissues. It is also believed that androgens play 45 an important role in modulating the secretory function of the lacrimal gland. [0006] Fifty percent of circulating testosterone is derived from direct ovarian secretion in the thecal cells under the control of luteinizing hormone. The other half is derived from peripheral conversion of adrenal androgen precursors dehydroepiandrosterone, androstenedione, and dehydroepiandrosterone sulfate. Testosterone can also be converted to dihydrotestosterone or estradiol. Thus, testosterone serves as both a hormone and as a prohormone. 50 [0007] Testosterone circulates in the blood 98% bound to protein. In women, approximately 66% of the binding is to the high-affinity sex hormone binding globulin. The remaining 34% is bound weakly to albumin. Thus, a number of measurements for testosterone are available from clinical laboratories. The term "free" testosterone as used herein refers to the fraction of testosterone in the blood that is not bound to protein. The term "total testosterone" or "testosteron e" as used herein means the free testosterone plus protein-bound testosterone. The term "bioavailable testosterone" as 55 used herein refers to the non-sex hormone binding globulin bound testosterone and includes that weakly bound to albumin. The order of affinity for the steroids most strongly bound by sex hormone binding globulin is dihydrotestosterone > testosterone > androstenedione > estrogen. Sex hormone binding globulin weakly binds dihydrotestosterone, but not dihydrotestosterone sulfate. Table 1 shows the approximate hormonal levels in normal pre-menopausal women. 2 EP 2 283 865 A1 Table 1: Hormone Levels in Normal Pre-Menopausal Women Hormone Mean sd Median Range 5 Testosterone (nmol/L) 1.20 0.69 0.98 0.4 - 2.7 Free testosterone (pmol/L) 12.80 5.59 12.53 4.1 - 24.2 % Free testosterone of total testosterone 1.4 1.1 1.1 0.4 - 6.3 Luteinizing hormone (IU/L) 7.2 3.3 6.7 3.0 - 18.7 10 Follicle stimulating hormone (IU/L) 4.7 3.6 4.2 1.5 - 21.4 Sex hormone binding globulin (nmol/L) 66.1 22.7 71.0 17.8 - 114.0 [0008] However, there is no general consensus on what constitutes "testosterone deficiency" in women because 15 historically it has been impossible to develop assays capable of measuring such small hormonal levels. This is especially true when measuring free or bioavailable testosterone levels. Consequently, currently available laboratory evaluations, including measuring total, free, and bioavailable serum testosterone levels, have not been used extensively to identify hypoandrogenic women. 20 B. Androgen Administration in Women [0009] In comparison to other hormone deficiency states, testosterone deficiency in women has been largely ignored as a clinical entity. Nevertheless, there exist well-defined patient populations where androgen production is clearly 25 deficient and where associated symptomatology has been described, including, for example, young oophorectomized/ hysterectomized women, post-menopausal women on estrogen replacement therapy, women on oral contraceptives, women with adrenal dysfunction, women with corticosteroid-induced adrenal suppression, and human immunodeficiency virus-positive women. [0010] Despite the clear benefits of administering testosterone to both normal and testosterone deficient women, almost all of the testosterone delivery preparations for human use are designed for hypogonadal men who require 30 significantly greater amounts of testosterone than a testosterone deficient